JP2008506674A - Combination of statin and bronchodilator - Google Patents

Abstract

  The present invention provides a medicament comprising a combination of bronchodilators, corticosteroids, and HMG-CoA reductase inhibitors in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD).

Description

FIELD OF THE INVENTION The present invention provides a medicament comprising a combination of bronchodilators, glucocorticosteroids, and HMG-CoA reductase inhibitors in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD). To do.

BACKGROUND OF THE INVENTION The diagnosis and management of many diseases both focus on typical diagnostic criteria and manifestations that are characteristic of a particular disease, for obvious reasons. And distinguish it from others). Examples are joint-related signs and symptoms in rheumatoid arthritis (RA) and pulmonary function tests in COPD.

  However, many diseases are often regarded as “other” diseases because they have significant co-morbidity, ie they are neither unique nor characteristic of primary diseases. For example, cardiovascular comorbidities are often seen as nonspecific and not directly related to primary diseases such as RA or COPD. However, comorbidities are as important as traditional treatment strategies for primary diseases, both in terms of patient quality of life and social costs.

  Chronic obstructive pulmonary disease (COPD) is a term used to describe patients with irreversible airway obstruction usually associated with chronic bronchitis and emphysema and is clearly epidemiologically related to smoking. COPD is characterized by both an accelerated decline in lung function and a condition called exacerbation and an acute exacerbation of exercise capacity. Thus, the disease is severe and progressive, often leading to severe respiratory impairment, hypoxemia, and ultimately death. COPD is the fourth leading cause of death in industrialized societies, placing a heavy burden on patients, their history, medical resources, and society. In western countries, COPD is predominantly seen among smokers, but in other parts of the world it appears to be caused by infection and indoor cooking. COPD is a disease in which inflammation and damaged mucosal immune defenses induced by smoking can contribute to comorbidities. Systemic inflammation remains active long after quitting smoking.

There are so many patients with COPD that the disease is difficult to treat. There are treatments that are effective in bronchospasm, symptoms, quality of life, and exacerbations, but there is no treatment that slows progressive and accelerated loss of lung function. The primary goal of treatment is to delay disease progression, and smoking cessation is the most important process to achieve this. However, not all COPD patients can quit or want to smoke, and even if the patient quits smoking, airway obstruction is almost always gone. In these cases, some relief can be obtained by pharmacological treatment. To date, in a few groups, pharmacological treatments have been tested, for example with bronchodilators and glucocorticosteroids, but with different results in COPD. A series of bronchodilators mainly include short-acting and long-acting anticholinergics and β ₂ -agonists. Treatment with glucocorticosteroids has been problematic, but the introduction of treatments that combine long-acting β ₂ -agonists (eg formoterol and salmeterol) together with glucocorticosteroids (eg budesonide and fluticasone propionate) New pharmacological tools are now available. In recent years, combination products containing long acting β ₂ -agonists and glucocorticosteroids, such as formoterol / budesonide (AstraZeneca), and salmeterol / fluticasone propionate (GSK) have become available.

  Furthermore, recent anti-inflammatory drugs developed for specific disease signs and symptoms cannot be optimized for long-term treatment of simultaneous systemic inflammation, which is presumed to be involved in many of the comorbidities. Such treatment should be able to reduce ongoing systemic inflammation, but be well tolerated and safe.

DESCRIPTION OF THE INVENTION Although many experts have expressed a need for new treatments for all aspects of COPD, they specifically prevent or at least reduce the declining of the disease over time. It is important to find a way to do it.

Some inflammatory mediators are likely related to COPD because many inflammatory cells are activated. For example, in medical procedures for the treatment of asthma, action on a single mediator does not succeed in developing new therapies. Compared to asthma, the mediators involved in COPD are different and therefore different drugs need to be developed. The targets for COPD, leukotriene B ₄ inhibitors, chemokine antagonists, neutrophil elastase, phosphodiesterase-4 inhibitors, cathepsins, matrix metalloproteinase (MMP), protease inhibitors, and many others is there. There is strong evidence to suggest that lung injury associated with COPD is caused by an imbalance between proteases.

  Matrix metalloproteinases can degrade all components of the extracellular matrix of lung parenchyma, including elastin, collagen, proteoglycan, laminin, and fibronectin (FASEB J, 12 1075 (1998)). Several non-selective MMP inhibitors have been developed, but side effects can be a problem with long-term use. More selective inhibitors of individual MMPs such as MMP-9 and MMP-12 are currently under development.

  Statins are increasingly being recognized as anti-inflammatory agents. Schoenbeck and Libby (Circulation, 109 (suppl. II), II-18-26 (2004)) is an anti-inflammatory agent for statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) We argue for this by examining in vitro and in vivo evidence. These authors say nothing about any relationship to the use of statins for any kind of respiratory disease.

  Statins are most commonly used as antihyperlipidemic compounds. Examples are lovastatin, rosuvastatin (CrestorTM, AstraZeneca), pravastatin (PravacholTM, Bristol-Myers Squibb), simvastatin (ZocordTM, Merck), itavastatin, cerivastatin, Fluvastatin, atorvastatin (Lipitor ™, Pfizer), and mevastatin. WO 00/48626 (Univ. Of Washington) provides a composition comprising an HMG-CoA reductase inhibitor (statin) at a concentration of less than 0.1 mg, and a method for treating lung diseases comprising COPD with a statin aerosol formulation is doing.

  EP 1 275 388 (Takeda) provides TNF-α inhibitors (statins) for the prevention and treatment of TNF-α related diseases such as inflammatory diseases (including asthma and COPD).

The statin cerivastatin has been shown to reduce the inflammatory activity of alveolar macrophages from patients with chronic bronchitis (Circulation 101 (2000), 1760). Studies with patients receiving statins (using specific patient inclusion criteria) showed that the initiation of statin treatment is responsible for a significant improvement in FEV ₁ decline rates not related to tobacco use factors . The slope of baseline FEV ₁ before statin administration was −109.2 ml / yr, and after statin treatment, the slope was −46.7 ml / yr (Chest, 120 (4), suppl, p291S (2001). )).

  We show that combinations of HMG-CoA reductase inhibitors (preferably statins), bronchodilators, and glucocorticosteroids given individually, sequentially or simultaneously can enhance the effects of each component. It has also been found to produce a better effect than conventional COPD treatment. The therapeutic effect is observed with respect to the rapid decline in lung function that is a hallmark of COPD, and the effect can be observed with respect to systemic inflammation characteristic of COPD. The long acting of the combination according to the invention is preservation of pulmonary function and less than presumed comorbidities (based on effects on systemic inflammation).

In a first aspect, the present invention provides:
(a) one or more first active ingredients that are statins, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or one or more second active ingredients that are solvates of the salt; and optionally,
(c) one or more third active ingredients which are glucocorticosteroids, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
Are provided in a mixture or individually.

  The combinations of the present invention can be used for the treatment of respiratory diseases such as asthma, COPD, and fibrolytic diseases such as systemic scleroderma, alveolitis, sarcoidosis, and idiopathic pulmonary fibrosis.

  Pharmacologically active agents according to the invention include statins such as lovastatin, rosuvastatin (CrestorTM, AstraZeneca), pravastatin (PravacholTM, Bristol-Myers Squibb), simvastatin (ZocordTM, Merck), Itavastatin, cerivastatin, fluvastatin, atorvastatin (Lipitor ™, Pfizer) and mevastatin.

  Suitable glucocorticosteroids are budesonide, fluticasone (eg as propionate), mometasone (eg as furan carboxylate), beclomethasone (eg as 17-propionate or 17,21-dipropionate), Ciclesonide, loteprednol (e.g. as etabonate), etiprednol (e.g. as dicloacetate), triamcinolone (e.g. acetonide), flunisolide, zoticasone, flumoxonide, flofoxonide (butixocort) (eg as propionate), prednisolone, prednisone, tipredane, steroid esters (I) as described in WO 2002/12265, WO 2002/12266 and WO 2002/88167: eg 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester And 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo-androst-1,4-diene- 17β-carbothioic acid S-fluoromethyl ester, steroid ester (II) described in DE 4129535 and the like.

Preferably, the bronchodilator is a long acting β ₂ -agonist. Suitable long acting β ₂ -agonists are salmeterol, formoterol, bambuterol, TA 2005 (2 (1H) -quinolone, 8-hydroxy-5- [1-hydroxy-2-[[2- ( 4-Methoxy-phenyl) -1-methylethyl] -amino] ethyl] monohydrochloride, chemically identified as [R- (R ^* , R ^* )] and also Chemical Abstract Service Registry Number 137888-11-0 And disclosed in U.S. Pat.No. 4.579.854 (= CHF-4226, carmoterol), QAB149 (CAS no 312753-06-3; indacaterol), formanilide derivative (III) such as WO 2002 / 3- (4-{[6-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] oxy} -butyl) disclosed in 76933 Benzenesulfonamide, benzenesulfonamide derivative (IV), eg WO 2002/88 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy-methyl) phenyl] ethyl} amino) -hexyl] oxy} butyl disclosed in 167 Benzenesulfonamide, aryl aniline receptor agonists (V) disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives disclosed in WO 2004/032921, and the like. Anticholine compounds include ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, solifenacin (e.g. as succinate), imidafenacin, darifenacin, fesoterodine, glycopyrronium ( For example as bromide), mepenzolate (for example as bromide), quinuclidine derivatives, such as bromide 3 (R)-(2-hydroxy-2,2-dithien-2-ylacetoxy) -1-disclosed in US 2003/0055080 (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane and the like. Some of these compounds, if any, can be administered in the form of a pharmaceutically acceptable ester, salt, solvate (eg, hydrate), or solvate of the ester or salt. Both racemic mixtures, as well as one or more optical isomers of the above compounds are within the scope of the invention.

Suitable physiologically acceptable salts include acid addition salts derived from inorganic and organic acids, such as chloride, bromide, sulfate, phosphate, maleate, fumarate, citrate. , Tartrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, acetate , Succinate, lactate, glutarate, tricarbarate, hydroxynaphthalene-carboxylate (xinafoate), or oleate, or a solvate thereof.
The second active ingredient is preferably formoterol fumarate dihydrate or salmeterol xinafoate.

Desirable pharmacologically active statins for use in the present invention include rosuvastatin and atorvastatin. Desirable corticosteroids include mometasone furanate, ciclesonide, zoticasone, flumoxonide, steroid (I), steroid (II), fluticasone propionate and budesonide, and more desirably budesonide. Desirable pharmacologically active long acting β ₂ -agonists are salmeterol xinafoate, formanilide derivative (III), benzenesulfonamide derivative (IV) and formoterol (eg, fumarate dihydrate) Even more desirable is formoterol fumarate dihydrate. More desirable anticholinergic agents include tiotropium, tolterodine, and quinuclidine derivatives (described in US 2003/005580).

  Preferably, there is one active ingredient in each class, ie one statin, one bronchodilator, and one corticosteroid.

The desired combination is
Atorvastatin / formoterol fumarate dihydrate;
Rosuvastatin / formoterol fumarate dihydrate;
Pravastatin / formoterol fumarate dihydrate;
Simvastatin / formoterol fumarate dihydrate;
Atorvastatin / budesonide / formoterol fumarate dihydrate;
Rosuvastatin / budesonide / formoterol fumarate dihydrate;
Rosuvastatin / ciclesonide / formoterol fumarate dihydrate;
Atorvastatin / fluticasone propionate / salmeterol xinafoate;
Atorvastatin / ciclesonide / formoterol fumarate dihydrate;
Rosuvastatin / mometasone furoate / formoterol fumarate dihydrate; and rosuvastatin / fluticasone propionate / formoterol fumarate dihydrate;
including.

The most desirable combination is
Rosuvastatin / formoterol fumarate dihydrate;
Atorvastatin / budesonide / formoterol fumarate dihydrate; and rosuvastatin / budesonide / formoterol fumarate dihydrate;
It is.

Other desirable combinations are
Rosuvastatin / formoterol fumarate dihydrate / tiotropium bromide;
Atorvastatin / formoterol fumarate dihydrate / tiotropium bromide;
Atorvastatin / formoterol fumarate dihydrate / tolterodine;
Rosuvastatin / tiotropium bromide;
Atorvastatin / tiotropium bromide;
including.

According to the present invention, in the manufacture of a medicament for use in the treatment of respiratory diseases
(a) one or more first active ingredients that are statins, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or one or more second active ingredients that are solvates of the salt; and optionally
(c) one or more third active ingredients which are glucocorticosteroids, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
Are provided in a mixture or individually.

The present invention also provides
(a) one or more first active ingredients that are statins, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or one or more second active ingredients that are solvates of the salt; and optionally
(c) one or more third active ingredients which are glucocorticosteroids, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
In a mixture or separately, comprising administering to the patient a combination of therapeutically effective amounts.

  Effective amounts of the ingredients will depend largely on the particular compound used and the method of administration, as well as the weight and disease state of the individual being treated. The oral dose of statin is generally in the range of about 0.01 mg to about 200 mg, preferably 10 to 80 mg, more preferably 5 to 40 mg; for inhalation 0.001 mg to about 25 mg A dose range of 0.1 to 25 mg is even more preferred.

Suitable daily doses of long acting β ₂ -agonists range from 1 μg to 100 mg, depending on the potency of the respective compound, eg for formoterol the daily dose ranges from 1 to 100 μg The desired dose is 3 to 48 μg (as fumarate dihydrate). Suitable daily doses for corticosteroids range from 50 μg to 2000 μg, for example for budesonide the daily dose ranges from 50 μg to 1600 μg. The dose for inhalation of the anticholinergic agent is 1 μg to 300 μg, preferably for ipratropium bromide (Atrovent ™, Boehringer Ingelheim), the dose is 10 to 200 μg, and tiotropium (Spiriva ™, For Boehringer Ingelheim) the dose is 1 to 50 μg.

Suitably, the molar ratio of the second active ingredient to the third active ingredient is 1: 2500 to 12: 1.
The molar ratio of the second active ingredient to the third active ingredient is preferably 1: 555 to 2: 1, more preferably 1: 150 to 1: 1. The molar ratio of the second active ingredient to the third active ingredient is more preferably from 1: 133 to 1: 6. The molar ratio of the second active ingredient to the third active ingredient is most preferably from 1:70 to 1: 4.

  The compounds of the invention can be administered as a mixture, ie, together, or can be administered separately. When administered together, the components can be administered as a single pharmaceutical composition, eg, as a fixed combination that can be administered by inhalation. Alternatively, the components may be administered individually, ie one after the other, for example orally with the statin and the remaining two components by inhalation. The time interval for individual administration may be any administration that is several hours away from the immediate (one after another) administration.

  Examples of respiratory diseases that can be treated by the present invention include asthma, chronic obstructive pulmonary disease (COPD), systemic scleroderma, alveolitis, sarcoidosis, cystic fibrosis, fibrinous and pseudomembranous rhinitis, and idiopathic Including pulmonary fibrosis.

The present invention further provides:
(a) one or more first active ingredients that are statins, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or one or more second active ingredients that are solvates of the salt; and optionally
(c) one or more third active ingredients which are glucocorticosteroids, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
Is mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, to provide a method for producing the pharmaceutical composition of the present invention.

  The therapeutically active ingredient may be administered prophylactically as a prophylactic treatment or may be administered during the course of a medical condition as a therapeutic treatment.

  The pharmaceutical compositions are in the form of solutions, suspensions, fluoroalkane aerosols, and dry powder formulations, topically (eg to the lungs and / or airways, or to the skin); or, for example, tablets, capsules, syrups, Systemically administered by oral administration in the form of a powder or granules, or parenterally in the form of a solution or suspension, or subcutaneously, or rectally in the form of a suppository or foam, or transdermally Can be done.

  The composition used in the present invention optionally further comprises one or more pharmaceutically acceptable additives, diluents and / or carriers. The composition is preferably in the form of a dry powder for inhalation, wherein the particles of the pharmaceutically active ingredient have a mass median diameter of less than 10 μm.

  When administered separately, administration can be via another route. For example, statins can be administered orally and combined with steroids and β-agonists by inhalation, either as a powder or as an aerosol formulation, or as a formulation suitable for nebulization. The compounds can be delivered from a single chamber / cartridge, but can also be delivered from two or three chambers / cartridges with separate channels.

Biological Data As mentioned above, COPD is a chronic disease that is triggered by smoking in susceptible individuals. It is characterized by various respiratory symptoms such as shortness of breath, wet cough, wheezing. These symptoms can sometimes suddenly increase with acute exacerbations at various intervals. Respiratory infection is an important trigger for life-threatening exacerbations and has a significant impact on quality of life. Some drugs have shown some prophylactic effect on the frequency of exacerbations: for example in combination with inhaled corticosteroids (ICS), especially long acting beta-agonists (LABA). Symbicort®, a fixed combination of budesonide and formoterol, has been approved for the treatment of COPD based on symptoms, quality of life, and prevention of severe exacerbations. This effect was based on the most severe exacerbations: the need for hospitalization due to respiratory symptoms or the need for oral corticosteroid treatment.

In a post hoc analysis of a long-term clinical trial of COPD, an inhibitory effect on FEV ₁ decline was observed in patients treated with statins. This effect was not seen with any other treatment including ICS. For the above exacerbations, there was a synergistic effect of budesonide and formoterol provided as Symbicort®. The effects of statins on exacerbations were not described and were not expected. Surprisingly, we have found that the combination of formoterol and budesonide (Symbicort) on exacerbations can be further enhanced by statins.

Methods A meta-analysis was performed from two one-year clinical trials for moderate to severe COPD. Patients treated with budesonide (Pulmicort®), formoterol (Oxis®), formoterol + budesonide (Symbicort®), or placebo with statins as concomitant medications and The case where it was not accompanied was analyzed. The frequency of severe deterioration defined as requiring treatment with oral corticosteroids was tested.

The result analysis results are shown in Table 1. A positive effect was demonstrated with the combination of formoterol and budesonide (Symbicort®) versus a single component (budesonide and formoterol, respectively), if the patient was treated with statins It was further strengthened. The lowest frequency of exacerbations is seen in patients who received Symbicort® + statins, 0.3 per year, representing a 75% reduction over the placebo group .

The positive effect of the combination of formoterol and budesonide (Symbicort®) treatment on COPD exacerbation was enhanced by statins, and the combination of formoterol and budesonide (Symbicort®), and statins The frequency of occurrence is lowest, corresponding to a 82% reduction over the placebo group.
The invention is illustrated by the following examples.

Example 1: Inhalation-dry powder Ingredients Formoterol (as fumarate dihydrate) 4.5 μg per dose
Budesonide 160μg
Rosuvastatin 1mg

Example 2: Inhalation-constant dose inhaler Ingredients Formoterol (as fumarate dihydrate) per dose 4.5 [mu] g
Budesonide 160μg
Rosuvastatin 1mg
HFA 227 50μl

Example 3: Inhalation-dry powder Ingredients Formoterol (as fumarate dihydrate) 4.5 μg per dose
Budesonide 160μg
Rosuvastatin 1mg
Lactose up to 1, 2, 5, 10 or 20 mg

Example 4: Inhalation / oral administration Aerosol formulation Ingredients per dose Formoterol (as fumarate dihydrate) 4.5 [mu] g
Budesonide 160μg
Tablet formulation Rosuvastatin 10mg

Example 5: Inhalation / oral administration Aerosol formulation Ingredients per dose Formoterol (as fumarate dihydrate) 4.5 [mu] g
Budesonide 160μg
Tablet formulation Rosuvastatin 20mg

Claims (17)

(a) one or more first active ingredients that are statins, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(b) a bronchodilator, a pharmaceutically acceptable salt or solvate thereof, or one or more second active ingredients that are solvates of the salt; and optionally
(c) one or more third active ingredients which are glucocorticosteroids, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
In a mixture or individually. The combination according to claim 1, wherein the statin (s) is selected from lovastatin, rosuvastatin, pravastatin, simvastatin, itavastatin, cerivastatin, fluvastatin, atorvastatin and mevastatin. The combination according to claim 1, wherein the statin is rosuvastatin. The combination according to claim 1, wherein the statin is atorvastatin. The combination according to any one of claims 1 to 4, wherein the bronchodilator (s) is a long acting β ₂ -agonist. The long-acting β ₂ -agonist (s) is salmeterol, formoterol, bambuterol, 2 (1H) -quinolone, 8-hydroxy-5- [1-hydroxy-2-[[2- (4-methoxy -Phenyl) -1-methylethyl] -amino] ethyl] monohydrochloride, [R- (R ^* , R ^* )], 3- (4-{[6-({(2R) -2- [3- (Formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] oxy} -butyl) -benzenesulfonamide, or 3- (4-{[6-({(2R) -2-hydroxy- 2- [4-Hydroxy-3- (hydroxy-methyl) phenyl] ethyl} amino) -hexyl] oxy} butyl) benzenesulfonamide and pharmaceutically acceptable salts or solvates thereof, or solvates of the salts 6. Any one of claims 1-5 selected from objects The combination of the described. The combination according to any one of claims 1 to 6, wherein the long-acting β ₂ -agonist is formoterol, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of the salt. . The combination according to any one of claims 1 to 7, wherein the long-acting β ₂ -agonist is formoterol fumarate dihydrate. The bronchodilator (s) is an anticholinergic agent, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of the salt. Combination. Anticholinergic (s) include ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, solifenacin (e.g. as succinate), imidafenacin, darifenacin, fesoterodine, Glycopyrronium (eg as bromide), mepenzolate (eg as bromide), quinuclidine derivatives, eg 3 (R)-(2-hydroxy-2,2-dithien-2-ylacetoxy) -1- (3-phenoxy bromide 5) Propyl) -1-azonia-bicyclo [2.2.2] octane and pharmaceutically acceptable salts thereof, or solvates of the salts thereof. combination. 11. A combination according to claim 10, wherein the anticholinergic agent is tiotropium bromide. Glucocorticosteroid (s) include budesonide, fluticasone, mometasone, beclomethasone, ciclesonide, loteprednol, etiprednol, triamcinolone, flunisolide, zoticazone, flumoxonide, rofleponide, butixocoat, prednisolone 9, prednisone 9 17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α-methyl-3-oxo-androst-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro- 11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, and And 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo-androst-1,4-diene-17β 5. Combination according to any one of claims 1 to 4, selected from carbothioic acid S-fluoromethyl esters and pharmaceutically acceptable salts thereof. The combination according to any one of claims 1 to 4, wherein the glucocorticosteroid is budesonide. 14. A combination according to any one of claims 1 to 13 for use in the treatment of respiratory diseases. 15. A combination according to any one of claims 1 to 14 for use in the treatment of COPD. (a) one or more first active ingredients that are statins, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(b) one or more second active ingredients that are bronchodilators, pharmaceutically acceptable salts or solvates thereof, or solvates of the salts;
(c) one or more third active ingredients which are glucocorticosteroids;
A method of treating a respiratory disease comprising administering to a patient a combination of therapeutically effective amounts, including in a mixture or individually. The method of claim 16, wherein the disease is COPD.